This invention relates generally to a method of treating humans with a decreased libido. More specifically, the invention relates to acute, bolus non-invasive administration of testosterone to enhance libido over a discrete period of time.
The presence of a normal amount of libido, defined as the urge to engage in sexual activity, is an important component of an individual""s well-being. In both men and women the primary naturally occurring hormone responsible for libido is testosterone. In males, the baseline testosterone level is a relatively constant throughout life, decreasing slowly in old age. In contrast, women elaborate testosterone only as part of the process of ovulation. Each maturing follicle produces testosterone at the mid-point of the menstrual cycle, consistent with observations that female libido peaks with ovulation. As a woman ages, the number of maturing follicles per month decreases, and there is a decreasing total amount of testosterone produced. A common complaint of post menopausal women is decreased libido. This decrease in libido is characterized by a lack of interest in sexual intercourse, the lack of ability to achieve orgasm, or decrease in intensity of orgasm. It is important to note that this decrease in libido is often associated with a profound sense of loss of a once normal and active interest in sexual activity. Low levels of testosterone in, e.g., hypogonadal men are associated with lack of libido and absence of erections. They respond to therapy with exogenous testosterone (Cunningham et al., J Clin Endocrinol Metab, (March 1990) 70:792-7; Behre et al., J Clin Endocrinol Metab, (November 1992) 75:1204-10; and women also respond to testosterone therapy, see Tuiten et al., Arch. Gen. Phychiatry, (February 2000) 57:149-153.
Clinicians frequently confronted with the problem of managing female patients presenting with decreased libido have limited tools to address the problem. Testosterone is available as an oral preparation and can be given, for instance, in combination with estrogen to restore testosterone levels. However, the replacement of the once pulsatile endogenous delivery of testosterone with the sustained blood level of the hormone produces unwanted side effects. Women taking testosterone for a few weeks typically begin to complain of the emergence of secondary sexual characteristics such as unwanted body hair, oily hair, and, with prolonged a use, deepening voice. For this reason, oral testosterone replacement therapy is not a practical solution for most patients with decreased libido.
Other forms of testosterone replacement therapy for women are being explored. A transdermal patch capable of delivering a steady rate of testosterone is being tested for use in women. As with oral testosterone replacement therapy, the study state blood levels of testosterone produced via transdermal delivery are likely to be associated with the same side effect profile issues.
It is recognized that testosterone in females decreases with age (Human Biology, May 1980, volume of 52, No. 2, pages 181-0191.). It is also known that sexual motivation in post menopausal women is associated with the levels of exogenously introduced testosterone (Psychosomatic Medicine volume 47, No. 4, 1985). Further, providing intravenous testosterone to women as part of clinical studies is known (American Journal of Obstetrics and Gynecology, December 1986 pages 1288 to 1292).
A transdermal patch for men is sold by Alza Corporation under the name of Testoderm(copyright). An injectable for intramuscular injectable is sold by Bristol-Meyers Squibb Company under the name Delatestryl(copyright), and by Star under the name Virilon(copyright) IM. While these dosage forms may increase steady state levels of testosterone in men, they do not result in the physiologically correct pulsatile release that occurs in men with normal testosterone production. A bolus delivery of testosterone that provides an approximation to the pulsatile delivery yielding short brief peaks that can provide the physiological stimulus for increase of sexual desire and improved erectile function.
A method of increasing the libido of a woman over a discrete period of time (e.g. 30-240 minutes) by the administration of testosterone is disclosed. The method of the invention does not maintain therapeutic levels of testosterone over long periods e.g. days, weeks or months. Because the method of the invention only maintains therapeutic levels over a short period the adverse side effects of long term testosterone treatment are avoided.
The testosterone formulation may be comprised of a reduced version of testosterone having been reduced by 5xcex1-reductase to 5xcex3-dihydroxytestosterone which is delivered in a bolus dose. The testosterone formulation may be administered in a variety of different ways, e.g. may be aerosolized preferably producing particles which have a size in a range of from about 1 to 3 microns which can be inhaled into areas of the lung where they can readily enter the blood stream.
An aerosol containing testosterone or its reduced version 5-xcex3-dihydrotestorone is inhaled into the lungs of a patient. Once inhaled, particles of the drug deposits on lung tissue and from there enter the patient""s circulatory system and thereby increase the patient""s serum testosterone level. The percentage increase in the patient""s testosterone level will vary depending on the needs of the patient. However, the patient""s normal baseline serum testosterone level is preferably increased 25% or more and more preferably 100% or more. By preferably providing the testosterone in a reduced form i.e. 5xcex1-dihydroxytestosterone because the delivery is by inhalation the patient""s serum level of an active form of the hormone is quickly raised to a desired level e.g. in thirty minutes or less, more preferably fifteen minutes or less. When the patient""s blood serum level of the active form of the hormone is raised to a desired level the patient""s libido is increased. The increased level gradually subsides (as the hormone is metabolized and cleared) thereby avoiding the adverse side effects generated by maintaining enhanced hormone levels over long periods.
An aspect of the invention is a method of increasing the libido of an adult human female patient by the administration of a bolus dose of testosterone which quickly increases the level of testosterone in the patient for a relatively brief time.
Another aspect of the invention is a method of treatment whereby testosterone or derivative thereof is aerosolized, inhaled and provided to the circulatory system of the patient at levels sufficient to increase libido (over a short period of time) and propensity for orgasm.
Another aspect of the invention is to combine bolus delivery of testosterone with additional treatment such as a topical cream applied to the vaginal area to increase blood flow to that area.
An advantage of the invention is that the testosterone levels are raised within minutes of administration (preferably 30 minutes or less) and return to normal levels within hoursxe2x80x94preferably in less than four hours.
Another advantage is that the administered testosterone is quickly metabolized allowing the patient""s testosterone levels to return to normal thereby avoiding the adverse effects of long term administration.
A feature of the invention is that aerosolized particles of testosterone having a diameter of about 0.5 to 8 microns (preferably 1-3 microns) are created and inhaled deeply into the lungs thereby enhancing the speed and efficiency of administration.
It is an object of this invention to describe the utility of delivering testosterone or dihydrotestosterone by inhalation as a means of treating women with decreased libido and/or decreased propensity to have orgasms.
It is another object of this invention to describe liquid formulations (which includes suspensions) of testosterone and derivatives thereof such as 5xcex1-dihydrotestosterone appropriate for pulmonary delivery.
It is another object of this invention to describe how testosterone or dihydrotestosterone delivered via the lung can quickly increase plasma levels substantially beyond baseline levels for the patient.
It is another object of this invention to describe the blood levels of testosterone or dihydrotestosterone required for rapid onset of a normal to enhanced libido in men or women with baseline decreased libido.
It is another object of this invention to describe the time course of inhalation of testosterone or dihydrotestosterone and the onset of increased libido in women or men suffering from decreased libido.
It is another object of this invention to describe how the pulsatile delivery of testosterone or specifically dihydrotestosterone as replacement therapy for women with decreased libido is associated with a decreased incidence of side effects (secondary sexual characteristics) commonly associated with traditional testosterone replacement therapy which produces a steady state level of the hormone.
It is another object of this invention to provide men with a pulsatile delivery of testosterone which approximates the natural physiological release of testosterone, in contrast to the existing delivery systems for testosterone such as transdermal patches or long acting injections containing esters of testosterone.
Other aspects of the invention include bolus (i.e. fast delivery and short acting effects) delivery of testosterone by any means including nasal delivery, rapid transdermal delivery which may be with absorption enhancers, and/or abrasive transdermal systems, microneedle systems, and topical creams, which systems may be used in various combinations.
The delivery of testosterone by inhalation provides, for the first time, the means for non-invasively delivering clinically relevant amounts of testosterone on demand near the time of planned intercourse.
It is an object of the invention to provide a method of treatment of erectile dysfunction in a patient comprising the steps of aerosolizing a formulation comprising sildenafil citrate, inhaling the aerosolized formulation into the lungs of a patient, and allowing the particles of sildenafil citrate to deposit on lung tissue and enter the patient""s circulatory system.
It is an object of the invention to provide an aerosolized formulation comprised of sildenafil citrate and a carrier, the aerosol being characterized by particles having a diameter in the range of about 1.0 micron to 5.0 microns making up 50% or more of the aerosol particles.
It is an object of the invention to provide a kit comprising an aerosol delivery device and a formulation comprising a testosterone, sildenafil citrate, or a combination thereof.
It is an object of the invention to provide a kit comprising two aerosol delivery devices and two formulations, a first formulation comprising a testosterone for use by a women, and a second formulation comprising a testosterone, sildenafil citrate, or a combination thereof, for use by a man.
These and other aspects, objects, advantages, and features of the invention will become apparent to those skilled in the art upon reading this disclosure.
The terms xe2x80x9ctestosteronexe2x80x9d, xe2x80x9ca testosteronexe2x80x9d and the like are used interchangeably here and are intended to mean the naturally occurring hormone known as testosterone having the chemical name 17-xcex2-hydroxyandrost-4-en-3-one which may be isolated and purified from nature or synthetically produced in any manner. The terms also comprise pharmaceutically acceptable esters, i.e., compounds where the xe2x80x9cHxe2x80x9d of the xe2x80x9cOHxe2x80x9d group is replaced with an alkyl group, e.g. propionate, cypionate and enanthate. Other pharmaceutically acceptable derivatives include methyltestosterone, methandrostenolone, fluovymesterone and danazol. A number of pharmaceutically useful derivatives of testosterone which are intended to be encompassed by the term testosterone as used here are disclosed within the Physician""s Desk Reference (most recent edition) as well as Harrison""s Principles of Internal Medicine. In addition, applicants refer to U.S. Pat. No. 5,536,714 issued Jul. 16, 1996; U.S. Pat. No. 5,824,668 issued Oct. 20, 1998; U.S. Pat. No. 3,980,638 issued Sep. 14, 1996; U.S. Pat. No. 4,031,117 issued Jun. 21, 1977; U.S. Pat. No. 4,085,202 issued Apr. 18, 1978; U.S. Pat. No. 4,197,286 issued Apr. 8, 1980; U.S. Pat. No. 4,507,290 issued Mar. 26, 1985 and U.S. Pat. No. 5,622,944 issued Apr. 22, 1997 all of which are incorporated herein by reference to disclose and describe testosterone derivatives and formulations.
The terms xe2x80x9creduced testosterone,xe2x80x9d xe2x80x9cdihydrotestosteronexe2x80x9d and the like are used interchangeably here and are intended to encompass the commonly occurring reduced version of testosterone having been reduced by 5xcex1-reductase to 5xcex1-dihydroxytestosterone which is also referred to here as dihydrotestosterone or simply xe2x80x9ca testosterone.xe2x80x9d A dihydrotestosterone may be isolated from nature but is preferably synthetically produced and purified. Testosterone USP is a white or creamy-white crystalline powder having a molecular weight of 288.43.
The terms xe2x80x9candrogen,xe2x80x9d xe2x80x9candrogenic hormonexe2x80x9d and the like are used interchangeably here and are intended to encompass any agent which stimulates activity of the accessory male sex organs and specifically is intended here to cover xe2x80x9ca testosteronexe2x80x9d as well as a xe2x80x9creduced testosteronexe2x80x9d as defined above.
The terms xe2x80x9cdiameterxe2x80x9d, xe2x80x9cparticle diameterxe2x80x9d and the like are used interchangeably herein to refer to particle size as given in the xe2x80x9caerodynamicxe2x80x9d size of the particle. The aerodynamic diameter is a measurement of a particle of unit density that has the same terminal sedimentation velocity in air under normal atmospheric conditions as the particle in question. This is pointed out in that it is difficult to accurately measure the diameter of small particles using current technology and the shape of such small particles may be continually changing. Thus, the diameter of one particle of material of a given density will be said to have the same diameter as another particle of the same material if the two particles have the same terminal sedimentation velocity in air under the same conditions. In connection with the present invention it is important to have particles which do not have too large of a diameter so that the particles can be inhaled deeply into the lungs and thereby deposited on lung tissue and transferred into the patient""s circulatory system. It is equally important not to have particles which are too small in that such particles would be inhaled into the lungs and then exhaled without depositing on the lung tissue in the same manner that particles of smoke can be inhaled and exhaled with only a small amount of the particles being deposited on the lung tissue. An acceptable range for particle diameter is in the range of 0.5 to 12 microns, preferably 0.5 to 8 microns and more preferably 1 to 3 microns.